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SIRT6 Recruits SNF2H to DNA Break Sites, Preventing Genomic Instability through Chromatin Remodeling
Open accessAbstract
DNA damage is linked to multiple human diseases, such as cancer, neurodegeneration, and aging. Little is known about the role of chromatin accessibility in DNA repair. Here, we find that the deacetylase sirtuin 6 (SIRT6) is one of the earliest factors recruited to double-strand breaks (DSBs). SIRT6 recruits the chromatin remodeler SNF2H to DSBs and focally deacetylates histone H3K56. Lack of SIRT6 and SNF2H impairs chromatin remodeling, increasing sensitivity to genotoxic damage and recruitment of downstream factors such as 53BP1 and breast cancer 1 (BRCA1). Remarkably, SIRT6-deficient mice exhibit lower levels of chromatin-associated SNF2H in specific tissues, a phenotype accompanied by DNA damage. We demonstrate that SIRT6 is critical for recruitment of a chromatin remodeler as an early step in the DNA damage response, indicating that proper unfolding of chromatin plays a rate-limiting role. We present a unique crosstalk between a histone modifier and a chromatin remodeler, regulating a coordinated response to prevent DNA damage.
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“The recruitment of SIRT6 to sites of DNA damage helps to remodel the local chromatin environment through deacetylation of H3K56 and allow DNA repair machinery to access the DNA (Toiber et al., 2013).”
From The Aging Epigenome (2016) · cites this paper as Toiber et al., 2013
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1 retracted
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Metadata
- Authors
- Toiber, D., Erdel, F., Bouazoune, K., Silberman, D. M., Zhong, L., Mulligan, P., Sebastian, C., Cosentino, C., Martinez-Pastor, B., Giacosa, S., D’Urso, A., Näär, A. M., Kingston, R., Rippe, K., & Mostoslavsky, R.
- Affiliations
- Harvard University (US)
- German Cancer Research Center (DE)
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2013-08
- Volume
- 51
- Issue
- 4
- Pages
- 454-468
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC3761390
- OpenAlex
- W2055373932
- Cited by
- 381
- References
- 47
- Citations by year
- 2026: 18 · 2025: 25 · 2024: 19 · 2023: 28 · 2022: 27 · 2021: 35 · 2020: 38 · 2019: 33 · 2018: 28 · 2017: 25 · 2016: 45 · 2015: 25 · 2014: 30 · 2013: 5
- FWCI
- 15.66
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- CONICET Digital (CONICET) (submittedVersion, cc-by-nc-nd)
- Funders
- Ellison Medical Foundation
- Fondazione Umberto Veronesi
- National Institutes of Health
- National Institute of General Medical Sciences (GM093072-01, R01GM093072)
- Congressionally Directed Medical Research Programs
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- SIRT6, SNF2H, chromatin remodeling, DNA double-strand breaks, DNA damage response, genomic instability, 53BP1, BRCA1, histone deacetylase, chromatin accessibility, DNA repair
- MeSH terms
- Adenosine Triphosphatases, Animals, Cells, Cultured, Cerebral Cortex, Chromatin, Chromosomal Proteins, Non-Histone, DNA Damage, DNA Repair, Hippocampus, Histones, Humans, Nucleosomes, Mice, Knockout, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Sirtuins, Chromatin Assembly and Disassembly, Genomic Instability, Chromatin Immunoprecipitation, Immunoprecipitation, Mice
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